Unsaturated 2-oxa steroid derivatives and process for their preparation

ABSTRACT

THIS INVENTION RELATES TO NOVEL UNSATURATED 2-OXA STEROID DERIVATIVES OF THE FORMULA   6A-R,7-(X-O-)-2,4,6A,7,8,9,9A,9B,10,11-   DECAHYDROCYCLOPENTA(5,6)NAPHTHO(1,2-C)PYRAN   WHEREIN R IS ALKYL HAVING FROM 1 TO 6 CARBON ATOMS, X IS SELECTED FROM THE GROUP CONSISTING OF HYDROGN, ALKYL HAVING FROM 1 TO 5 CARBON ATOMS, ALKENYL HAVING FROM 3 TO 5 CARBON ATOMS, CYCLOALKYL HAVING FROM 5 TO 7 CARBON ATOMS, ARALKYL HAVING FROM 7 TO 11 CARBON ATOMS, ALKYLTHIOALKYL HAVING FROM 2 TO 5 CARBON ATOMS, ALKOXYALKYL HAVING FROM 2 TO 5 CARBON ATOMS, AND THE ACYL OF AN ORGANIC CARBOXYLIC ACID HAVING FROM 1 TO 18 CARBON ATOMS, AS WELL AS THE PROCESS OF PREPARING THE SAME. THESE COMPOUNDS HAVE AN ANABOLIC ACTION COUPLED WITH AN ANDROGENIC ACTION.

US. Cl. 260-343.2 15 Claims ABSTRACT OF THE DISCLOSURE This invention relates to novel unsaturated 2-oxa steroid derivatives of the formula wherein R is alkyl having from 1 to 6 carbon atoms, X is selected from the group consisting of hydrogen, alkyl having from 1 to carbon atoms, alkenyl having from 3 to 5 carbon atoms, cycloalkyl having from 5 to 7 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 4 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, as well as the process of preparing the same. These compounds have an anabolic action coupled with an androgenic action.

BENEFIT OF COPENDING APPLICATIONS This application is a continuation-in-part of our copending applications Ser. No. 603,094, filed Dec. 20, 1966, and Ser. No. 603,457, filed Dec. 21, 1966, both now abandoned.

OBJECTS OF THE INVENTION An object of the invention is the obtention of an unsaturated 2-oxa steroid derivative of the formula wherein R is alkyl having from 1 to 6 carbon atoms, X is selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, cycloalkyl having from 4 to 7 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 6 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms.

Another object of the invention is the development of a process for the production of the above unsatuarted 2-oxa -United States Patent 0 ice steroid derivatives which comprises the steps of condensing a 10 hydroxymethyl des A A -gonadiene-5- one of the formula R JOX wherein R is alkyl having from 1 to 6 carbon atoms, X is selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, cycloalkyl having from 4 to 7 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 6 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, with a lower alkyl haloacetate in the presence of zinc, reacting the resulting condensation products, a mixture of (l) a 5 alkoxycarbonylmethyl 10 hydroxymethyl des A- A -gonadiene of the formula wherein R and X have th above-assigned meanings and alkyl represents a lower alkyl, and (2) a 2-oxa-A -gonadiene-5-ol-3-one of the formula HO-CHzo Acyl wherein R is alkyl having from 1 to '6 carbon atoms and acyl represents the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, with a lower alkyl haloacetate in the presence of zinc, saponifying the resulting condensation products, a mixture of (1) a 5-alkoxycarbonylmethyl 10 hydroxymethyl des A-A -gonadiene of the formula R p Acyl EEO-CH2- wherein R and acyl have the above-assigned meanings and alkyl represents a lower alkyl, and (2) 2-oxa-A gonadiene-5-ol-3-one of the formula OH wherein R and acyl have the above-assigned meanings, by the action of a saponifying agent, reacting the resulting products, a mixture containing as a major part of a 2-oxa- A -gonadiene of the formula R W oX HO-CH2 wherein R is alkyl having from 1 to 6 carbon atoms, X is selected from .the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, cycloalkyl having from 5 to 7 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 6 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, and

, alkyl represents lower alkyl, and (2) a 2-oXa-A -gonadiene-5-ol-3-one of the formula wherein R is alkyl having from 1 to 6 carbon atoms, X is selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, cycloalkyl having from 5 to 7 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 6 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms.

A still further object of the invention is the obtention of a therapeutic composition containing a minor amount of the above 2-oxa steroid derivative and a major amount of a pharmaceutical carrier.

Another object of the invention is the development of a process for the treatment of warm-blooded animals with an anabolic and androgenic agent which comprises administering to said warm-blooded animals a daily dose of from 0.003 mg./kg. to 0.3 mg./kg. of the above 2-oxa steroid derivative.

These and other objects of the invention will become more apparent as the description thereof proceeds.

DESCRIPTION OF THE INVENTION wherein, here and later on, R is an alkyl radical having from 1 to 6 carbon atoms, and X is selected from the consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, cycloalkyl having from 5 to 7 carbon atoms, aralkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 4 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms.

In the general Formula I, the alkyl R is by preference one of the following: methyl, ethyl, propyl, butyl; the alkyl radical X which can include a hetero atom between 2 carbon atoms is advantageously the methoxymethyl or the methylthiomethyl and the acyl X is advantageously selected from the group consisting of the acyl of aliphatic, saturated or unsaturated, carboxylic acids or of aromatic or heterocyclic carboxylic acids, of hexahydrobenzoic acid, of cyclopentyl-, cyclohexyl-, or phenylacetic or propionic acids, of phenoxyalkanoic acids, of furan-Z-carboxylic acids, 5-ter.-butylfuran-2-carboxylic acids, of ,B-ketocarboxylic acids, among others.

Preferably, in the general Formula I, R can be methyl, ethyl and propyl; and X can be hydrogen, alkyl having from 1 to 5 carbon atoms such as methyl, ethyl, propyl, etc., alkenyl having from 3 to 5 carbon atoms, such as A -propenyl, methylallyl, dimethylallyl, etc., cycloalkyl having from 5 to 7 carbon atoms, such as cyclopentyl or cyclohexyl, cycloalkylalkyl having from 6 to 11 carbon atoms, such as hexahydrobenzyl or substituted hexahydrobenzyl, alkoxyalkyl having from 2 to 5 carbon atoms, such as methoxymethyl, ethoxyethyl, etc., alkylthioalkyl having from 2 to 5 carbon atoms, such as methylthiomethyl and the like, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms selected from the group consisting of alkanoic acids, such as acetic acid, propionic acid, lauric acid, etc., alkenoic acids such as oleic acid, etc., benzoic acid, hexahydrobenzoic acid,

cycloalkylalkanoic acids, such as cyclopentyl-, cyclohexyl-, acetic or propionic acids, etc., phenylalkanoic acids such as phenylacetic acid, phenylpropionic acid, etc., heterocyclic carboxylic acids such as furan-Z-carboxylic acid, S-ter-butylfuran-Z-carboxylic acids, etc., and ,B-ketoalkanoic acids such as acetylacetic acid, etc.

The compounds of the general Formula I possess useful pharmacological properties. In particular, these compounds distinguish themselves from 2 oxa 17a methyl 17B hydroxy 19 nor androstane-3-one (Presse Medicale [1963] 71, pp. 1319-20) by a far superior anabolic action.

The compounds of the general Formula I are particularly endowed with a high anabolic activity, and, in addition, for some of them, an androgenic activity.

Among the compounds of the general Formula I, the following are especially interesting:

13fl-methyl-17,3-acetoxy-2-oxa-A -gonatriene-3-0ne 13 B-methyl- 17,8- (methoxy) -methoxy-2-oxa-A -gonatriene-3-one l3 3-methyl-17,3-benzoyloxy-2-oxa-A -gonatriene-3-one 1Bil-ethyl-17;3-acetoXy-2-oXaA -gonatriene-3-one 1313-ethyl-l7B-benzoyloxy-2-oxa-A -gonatriene-3-one 13 B-methyl-17B-hexahydrobenzyloxy-Z-ox-a-M- gonatriene-3-one 13,8-methyl-17/S-benzyloxy-2-oxa-A -gonatriene-3-one 13 fl-rnethyl- 17,3- methylthio -methoxy-2-oxa-A gonatriene-fi-one 13/3-rnethyl-17,B-(3'-methyl-2-butenyloxy) 2-oxa-A gonatriene-3-one 13fi-methyl-l713-(2'-methyl) allyloxy 2-oxa-A -gonatriene-3-one.

Thus, 13fl-methyl-17fl-acetoxy-2-oxa-A -gonatriene- 3-one possesses important anabolic and androgenic actions which are quite superior to those of 19-nor-testosterone acetate. Moreover, it is active when given orally and its action is clearly superior to that of the 17a-methyl-19-nortestosterone.

IBfi-methyl-17p-(methoxy)-methoxy-2-oxa-A -gonatriene-3-one possesses an important anabolic action and a moderated androgenic action. The anabolic activity 01". this product is very superior to that of 17a-methyltestosterone. A daily dose of 207 of 13 3 methyl 1713- (methoxy)-methoxy 2-oxa-A -gonatriene-3-one has already a strong anabolic action on the animal, and its androgenic effect is only slightly perceptible.

13(3 methyl-17,3-benzoyloxy-2-oxa-A -gonatriene-3- one possesses important anabolic and androgenic actions which are quite superior to those of l9-nor-testosterone acetate and 17u-methyl-19-nor-testosterone both when administered orally and subcutaneously.

13,9 ethyl 17 8 acetoxy-2-oxa-A -gonatriene-3-one possesses a clearly superior anabolic action than 19-nortestosterone acetate and has a much greater androgenic action.

The process for the preparation of the compounds of the general Formula I is characterized in that a lO-hydroxymethyl-des-A-A -gonadiene-S-one of the general Formula II is condensed with a lower alkyl haloacetate in the presence of zinc. The resultant condensation product, a mixture of a hydroxy S-alkoxycarbonylmethyl-1.0-

hydroxy methyl des A-A -gonadiene of the general Formula III R 3am HOCH2 0 H III and 2-oxa-A -gonadiene-5-ol-3-one of the general Formula IIIa OH IIIa is treated with a strong acid agent after optional saponification of the S-alkoxycarbonylmethyl derivative, and the desired 2-oxa-A -gonatriene-3-one of the general Formula I is isolated, which, in the desired case, is subjected, when the said compound comprises a 17-hydroxyl function, to the action of an esterification agent to form the corresponding 17-ester, or to the action of an etheri- *fication agent to form the corresponding 17-ether.

It is preferred to utilize the benzoate ester in the synthesis of the invention. However, the 17-ethers and the l7-alcohol can also be utilized. Among the 17-ethers are the l7/3-methoxy, the l7fl-ethoxy, and 17fl-allyloxy, the l7fi-methoxymethoxy, etc.

The execution of the process of the invention can also be characterized by the following points:

(1) The lower alkyl haloacetate is selected from the group consisting of methyl or ethyl bromoacetate, methyl or ethyl chloroacetate and methyl or ethyl iodoacetate.

(2) The strong acid agent is selected from the group consisting of a strong mineral acid, such as hydrochloric acid, sulfuric acid or perchloric acid, and a strong organic acid, such as p-toluene sulfonic acid or methane sulfonic acid.

(3) The esterification agent is selected from the group consisting of an organic carboxylic acid containing from 1 to 18 carbon atoms, and a functional derivative thereof such as an acid anhydride or an acid chloride.

(4) The esterification agent is a saturated or unsaturated alkyl halide, containing from 1 to 5 carbon atoms, possibly including an oxygen atom between two carbon atoms, such as methoxy-chloromethane or dialkylsulfoxide.

A variation of the process of the invention is characterized in that a 10-hydroxymethyl-l7fi-acyloxy-des-A- A -gQnadiene-S-one of the general formula 0 Acyl v 7 droxy alkoxycarbonylmethyl-IO-hydroxymethyl-17/3- acyloxy-des-A-A -gonadiene of the general formula and of a 17;8-acyloxy-2-oxa-A -gonadiene-5-ol-3-one of the general formula R O Acyl is treated with a saponification agent to obtain the corresponding l7-hydroxyl compound. The saponified mixture is subjected to the action of a strong acid agent, and the desired 2-oxa-A -gonatriene-17,8-ol-3-one is isolated, which, in this case, if desired, is subjected to the action of an esterification agent to form the corresponding 17-ester or to the action of an etherification agent to form the corresponding l7-ether.

The execution of the variation of the process of the invention can also be characterized by the following points:

(1) The saponification agent is an alkali metal hydroxide in the presence of a lower alkanol such as methanolic sodium or potassium hydroxide.

(2) The lower alkyl haloacetate, the strong acid agent, the esterification agent and the etherification agent are as given in the preceding.

The starting products of the present process of the general Formula II are obtained by the processes of formylating a des-A-A -gonene of the formula dehydrogenating the resulting 10-hydroxymethylene derivative and reducing the resulting l0-formyl derivative to obtain the starting products of the general Formula II, or of condensing an enamine of the formula The starting products of the Formula V goncne of the formula R (\l 0 Acyl wherein Acyl represents the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms and R has the above-assigned meaning, to obtain a IO-hydroxymethylene derivative of the Formula IV HOHC:

wherein R and acyl have the above-assigned meanings, or (B) condensing an enamine of the formula O Acyl 0 Acyl wherein R and R are selected from the group consisting of alkyl having from 1 to 8 carbon atoms, and, when taken together, alkylene having from 4 to 5 carbon atoms and alkylene-oxy-alkylene having 4 carbon atoms, and R and Acyl have the above-assigned meanings, with a mixed formic-acetic acid anhydride, hydrolyzing the resulting 10-hydroxymethylene iminium derivative of the formula O Acyl HOHC:

e R2l?= wherein R, R R and Acyl have the above-assigned meanings to obtain a IO-hydroxymethylene derivative of Formula IV, reducing said IO-hydroxymethylene derivative, reacting the 10-formy1-des-A-A -gonadiene-S-one thus formed, of the formula O Acyl wherein R and Acyl have the above-assigned meanings, with a ketalizing agent, saponifying the resultant diketal of the formula 0 Acyl wherein K is a ketal group, R and Acyl have the aboveassigned meanings, by the action of an alkaline agent, etherifying the resultant 17 3-01 derivative of the formula wherein K and R have the above-assigned meanings, by the action of a halogenide of the formula XHal, wherein Hal is a halogen atom other than fluorine, and X is as herein before defiined, subjecting the resultant 17-ether of the formula wherein R, K and X have the above-assigned meanings, to an acid hydrolysis, reducing the resultant -forrnyldes-A-gonadiene of the formula example ethyleneglycol. The reaction is conducted in the presence of an acid catalyst.

(b) The alkaline agent used in the saponification step is an alkali metal hydroxide, such as sodium or potassium hydroxide, in the presence of a lower alkanol such as methanol or ethanol.

(c) The etherification step is carried out in the presence of a basic agent, such as sodium hydride, in a polar solvent such as tetrahydrofuran, dimethylformamide or dimethylsulfoxide.

(d) The mixed hydride is selected from the group consisting of an alkali metal borohydride, such as sodium borohydride, and an alkali metal hydridotrialkoxoaluminate, such as lithium hydridotriisobutoxoaluminate. The reaction is preferably performed in aqueous dioxane in the first case, and in tetrahydrofuran in the second case.

The following examples will serve for a better comprehension of the invention without, however, limiting the scope of the invention in any manner.

EXAMPLE I Preparation of -methyl-17B-benzoyloxy-2-0Xa- A -gonatriene-3-one (A) Condensation: 3 gm. of 10-hydroxymethyl-13flmethyl -benzoyloxy-des-A-A -gonadiene-S-one (as described in US. patent application Ser. No. 603,094) were dissolved in 45 cc. of anhydrous benzene, then 3 gm. of zinc and an iodine crystal were added. Next, under good agitation and within the space of 10 minutes, 3 cc. of ethyl bromoacetate were introduced into the mixture heated approximately to reflux. The reaction was strongly exothermic. The reflux was maintained for about 10 minutes after the end of the introduction of the reactant.

The reaction mixture was then cooled. The organic solution was washed first with an aqueous iced solution of hydrochloric acid, then with Water, dried, distilled to dryness, and the residue obtained was subjected to chromatography through silica gel, 'with elution with a 50% mixture of benzene and ethyl acetate.

In this manner, 2.78 gm. of a mixture of S-hydroxy- 5 carboethoxymethyl-IO-hydroxymethyi-13fi-methyl-17flbenzoyloxy-des-A-A -gonadiene and 5 hydroxy 13B- methyl-17 3-benzoyloxy-2-oxa-A -gonadiene-3-one were isolated, which mixture was used as such in thefollowing step of the synthesis.

5 hydroxy 13B methyl-17fl-benzoyloxy-2-oxa-A gonadiene-3-one can be isolated from the mixture indicated above by crystallization from methanol. Its melting point was 226 C. with a specific rotation [a] =+39 (c.=0.5% in chloroform).

Analysis.Calculated for C H O (percent): Molecular weight =394.45. C, 73.07; H, 6.64. Found (percent): C, 73.0; H, 6.7.

This compound is not described in the literature.

(B) Acid treatment: 2.78 gm. of the raw mixture, obtained under (A), were dissolved in 20 cc. of benzene under an atmosphere of nitrogen; then 0.25 gm. of p-toluene sulfonic acid was added and the reaction mixture was heated at reflux for about 10 minutes.

The benzenic solution was washed first with an aqueous solution of sodium bicarbonate, then with water, dried, distilled to dryness, and in this way, 13;8-methyl-17B- benzoyloxy-2-oxa-A -gonatriene-3-one was obtained.

The product had a melting point of 186 to 187 C. and a specific rotation [a] =l13O.5 (c.=0.55% in chloroform).

This compound is not described in the literature.

EXAMPLE II Preparation of 13i3-methyl-17B-hydroxy-2-oxa- A -gonatriene-3-one (A) Condensation: This step was effected exactly in the manner as described in Example I.

(B) Saponification: 2.78 gm. of the raw mixture, obtained under (A), were dissolved in 27 cc. of methanol 1 1 under an atmosphere of nitrogen; then 2.8 cc. of potassium hydroxide solution were added and the reaction mixture was heated at reflux for one hour.

Thereafter, the reaction mixture was cooled and 3.5 cc. of hydrochloric acid were added thereto. Next, the reaction mixture was poured into water and extracted with methylene chloride. The extracts were washed first with a saturated aqueous solution of sodium bicarbonate, then with salt water, lastly with water, dried and distilled to dryness.

In this manner, 1.92 gm. of a product was isolated containing as a major part 135-methyl-5,17/3-dihydroxy-2-oxa- A -gonadiene-3-one, which product was used as such for the next step of the synthesis 13,8 methyl-5,17B-dihydroxy-2-oxa-A -gonadiene-3- one could be isolated from the raw product indicated above by subjecting it to chromatography through silica gell and by crystallization of the eluate from methanol. The melting point was 204 C.

Ultraviolet spectra (ethanol):

A 242243 mg, e=-18,200 Infrared spectra (chloroform):

11 lactone at 1,740 cmr This compound is not described in the literature.

(C) Acid treatment: 1.92 gm. of the raw product, obtained under (B), were dissolved in 10 cc. of methanol under an atmosphere of nitrogen. Then 2 cc. of chloroform and 1 cc. of concentrated hydrochloric acid were added, and the reaction mixture was allowed to stand for /2 hour at room temperature.

Thereafter, the reaction mixture was poured into water and extracted with methylene chloride. The organic extract was washed first with a saturated aqueous solution of sodium bicarbonate, then with salt water and lastly with pure water, dried and distilled to dryness.

The residue obtained was crystallized from ethyl acetate, thus obtaining 1.28 gm. of 13fl-methyl-17B-hydroxy-2- oxaA -gonatriene-3-one, which after recrystallization from methylethylketone, had a melting point of 222 C. and a specific rotation of [oz] =+26.9 (c.=0.69% in chloroform). The yield of crystallization amounted to 70% of the theory.

The product was insoluble in ether, slightly soluble in alcohol, and soluble in chloroform.

Ultraviolet spectra (ethanol):

x 230 mu, 5:5,720; 328 mu, =27,230 (N/ sodium hydroxide in ethanol):

8 232 mg and 304 mu Infrared spectra:

lactone--- at 1,706 crnr with a shoulder at 1,722 and 1,688 cm.-

Analysis.-Calculated for C H O (percent): Molecular weight=272.33. C, 74.97; H, 7.4. Found (percent): C, 74.9; H, 7.6.

This compound is'not described in the literature.

The 13,6 methyl-17/3-hydroxy-2-oxa-A J -gonatriene- 3-0ne as described in the preceding, was identical to the compound obtained by saponification of 13B-methyl-17fibenzoyloxy-2-oxa-A -gonatriene-3-one described in Example I. This'saponification can be effected in the following manner.

1 gm. of 13 3 methyl 17e-benzoyloxy-2oxa-A gonatriene-3-one was admixed with 10 cc. of methanol and 1 cc. of 10 N potassium hydroxide solution, and the mixture was heated at reflux for about 20 minutes. Thereafter, the reaction mixture was acidified by the addition of 1.5 cc. of concentrated hydrochloric acid, poured into water and extracted with methylene chloride.

The methylene chloride extract was washed first with a saturated aqueous solution of sodium bicarbonate, then with water, dried and distilled to dryness, and l3,6-methyl- 17,8-hydroxy-2-oxa-A -gonatriene-3-one was isolated.

1 2 EXAMPLE III Preparation of 1318-methyl-17.13-benzoyloxy-2-oxa- A -gonatriene3one 50.4 gm. of zinc and 1.18 gm. of iodine were introduced into a solution of 50.4 gm. of IO-hydroxymethyl- 136 methyl 175 benzoyloxy-des-A-A -gonadiene-5- one (obtained as described in Belgian Patent 691,404) in 765 cc. of benzene. Then a third of a solution of 50.4 cc. of ethyl bromoacetate in 114 cc. of benzene was added thereto, and the mixture was refluxed for 25 minutes. Next, the rest of the ethyl bromoacetate solution was added and the reflux was maintained for an additional 20 minutes. Then, the temperature was brought to 25 C. and the mixture was filtered. The filtrate was washed with benzene. The combined benzenic phases were washed first with an aqueous hydrochloric acid solution, then with water, dried over sodium sulfate and evaporated to dryness. The residue was subjected to chromatography through silica gel and eluated with a benzene-ethyl acetate mixture (5-5). In this manner, 24 gm. of amorphous product were recovered which was used as such for the remainder of the synthesis.

6 gm. of the amorphous product, previously obtained, were dissolved in 36 cc. of acetic acid. 3.6 cc. of 2 N hydrochloric acid were added and the mixture was agitated for 2 hours and 30 minutes at room temperature. Next, 12 cc. of water were added and crystallization commenced. cc. of a water-ice mixture were added and the mixture was again agitated for 30 minutes and finally vacuum filtered. The precipitate was washed with water and dried. Thus, 4.46 gm. of raw 13,8-methyl-l7B-benzoyloxy-2-0xa-A' -gonatriene-3-one were recovered.

The raw product was purified by chromatography through silica gel, elution with a benzene-ethyl acetate mixture (7-3) and by recrystallization with heating and cooling from ethyl acetate. 2.1 gm. of 13,8-methyl-17fibenzoyloxy 2-oxa-A -gonatriene-3-one were obtained with a melting point of 188 to 189 C.

Analysis.-Calculated for C H O (percent) Molecular weight=376.43. C, 76.57; H, 6.42. Found (percent):

Infrared spectra (chloroform):

absence of OH presence of benzoate presence of complexed carbonyl at- 1,72l l,709 1,692 Ultraviolet spectra (ethanol):

max. at 230 m E}" ,=524 max. at 324 m E}? ,=772 or e=29,100

The methyl 17,8 benzoyloxy 2-oxa-A gonatriene-B-one occurred in the form of pale yellow needles, soluble in chloroform, alcohol and methylene chloride and insoluble in Water.

The product had a melting point, determined on the Kofler block of 188 to 189 C. and a specific rotation [a] =+l29i2 (c.=1% in chloroform).

This compound is not described in the literature.

The 135 methyl 17;? benzoyloxy 2 oxa-A gonatriene-S-one may also be prepared in the following manner:

500 mg. of 13B-methyl-2-oxa-A -gonatriene-176-01- 3-one were dissolved in 2 cc. of pyridine. The solution was cooled to +5 C. and 0.75 cc. of benzoyl chloride were added, without exceeding +10 C. The mixture was agitated over 2 hours at +5 C. and then it was allowed to stand over a period of 17 hours in the refrigerator. Thereafter, 0.6 cc. of formic acid were added. The reaction mixture was agitated for one hour at +5 C. to +10 C., and then it was poured into a mixture of a saturated aqueous solution of sodium bicarbonate, water and ice. Next, the reaction mixture was extracted with methylene chloride. The methylene chloride phases were washed first with N hydrochloric acid, then with a saturated aqueous solution of sodium bicarbonate and lastly with water, then dried over sodium sulfate and distilled to dryness, in vacuo. 0.98 gm. of raw 13 3-methyl-17B- benzoyloxy-2-oxa-A -gonatriene-3-one were recovered, which was purified by chromatography through silica gel, elution' with a benzene-ethyl acetate mixture (7 3) and recrystallization from methanol. In this manner, 0.298 gm. of 13p methyl 17B benzoyloxy 2-oxa-A gonatriene-3-one were obtained, identical to that previously obtained.

In the same manner as described in Examples 1 and II, the work was conducted by starting with -hydroxymethylated tricyclic derivatives, but having in the 13- position an alkyl other than methyl such as ethyl, propyl, isopropyl, butyl, isobutyl, leading in the corresponding 2-oxa steroid derivative.

EXAMPLE IV Preparation of 13Bmethyl-17/3-acetoxy-2-oxa- A -gonatriene-3-one Under an atmosphere of nitrogen and at room temperature, 0.8 gm. of 13B-methyl-17B-hydroxy-2-oxa-A gonatriene-3-one were introduced into 3.2 cc. of pyridine. Then 1.6 cc. of acetic acid anhydride were added and the reaction mixture was agitated for 4 /2 hours.

The excess of the reactant was destroyed by addition of water, then the reaction mixture was again agitated for a few minutes, and then acidified with concentrated hydrochloric acid to bring about crystallization. Then, the mixture was diluted with water and agitated for one hour. The crystals were vacuum filtered and washed until the wash waters were neutral.

After drying, the raw product was subjected to chromatography through silica and eluated with a benzene-ethyl acetate mixture (11).

In this manner, with a yield of 87% of the theory, 13 8- methyl-l7,3-acetoxy-2-oxa-A -gonatriene-3-one was obtained which, after recrystallization from isopropanol, had a melting point of 110 C. and a specific rotation [a] =+6l (c.=0.56% in chloroform).

Ultraviolet spectra (ethanol):

. max' at 229-230 m e=6,160 and at 324111;.0, s=27,400

Infrared spectra (chloroform):

'y lactone at 1,708 and 1,689 cm.- C=C bond at 1,593 and 1,562 cmfl The product was insoluble in water, and soluble in ethanol and chloroform. I

Analysis-Calculated for C H O (percent): Molecular weight=3l4.37. C, 72.58; H, 7.05. Found (percent): C, 72.7; H, 7.1.

This compound is not described in the literature.

EXAMPLE V Preparation of l3B-methyl-17,8-(methoxy)-methoxy- 2-oxa-A -gonatriene-3-one 2.72 gm. of 13/3-methyl-17fl-hydroxy 2 oxa-A gonatriene-3-one were dissolved in 30 cc. of dimethylformamide, and 2 cc. of chloromethyl-methyl ether were added thereto. Then the mixture was allowed to stand for 2 hours at room temperature. Thereafter, again 2 cc. of chloromethyl-methyl ether were added and the mixture was allowed to react for 16 hours at room temperature. Next, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with methylene chloride. The combined organic phases were washed first with a sodium bicarbonate solution, then with water until the wash Waters were neutral, dried over sodium sulfate and concentrated to dryness under vacuum. By this method, 3.12 gm. of an oily product were recovered, which was subjected to chromatography through silica gel and eluted first with a chloroform-ethyl acetate mixture (1 to 1), then with a benzene-ethyl acetate mixture (7 to 3). In this way, 2.16 gm. of 13,8-methyl-l7/8- (methoxy)-methoxy 2 oxa-A -gonatriene-3-one were obtained, representing a yield of 70% of the theory. After recrystallization from isopropanol the product had a melting point of to 111 C. and a specific rotation [a] =+34 (c.=0.5% in chloroform).

Analysis.-Calculated for C H O (percent): Molecular weight=316'.38. C, 72.12; H, 7.65. Found (percent): C, 71.9; H, 7.7.

Ultraviolet spectra (ethanol):

1I1B.X

at 229-230 mg, s=6,000' and at 326 my, e=27,950 (ethanol-N/ 10 NaOH) max at 229 my, 6:3,800 and at 304 my, e=23,550

The product occurred in the form of clear yellow crystals, soluble in the usual organic solvents, and insoluble in water, in dilute aqueous acids and in dilute aqueous alkalis.

This compound is not described in the literature.

EXAMPLE VI Preparation of 13B-ethyl-17B-benzoyloxy-2-oxa- A -gonatriene-3-one STEP AP R'EPARA'TION OF 10HYDROXYMETHYLENE JOS\II3D- ETHYL-I7B-BENZOYLOXY-DES-A-A -GONENE-5- At room temperature, under agitation and an atmosphere of nitrogen 27.23 gm. of 5-pyrrolidino-l3fi-ethyl- 17/3-benzoyloxy-des-A-A -gonadiene (obtained according to the process described in US. Pat. No. 3,168,- 530) were dissolved in 272 cc. of dioxane and 136 cc. of tetrahydrofuran. Then, 20 cc. of triethylamine and, while maintaining the temperature between 0 C. and +5 C., 50 cc. of formic-acetic acid anhydride (obtained by the action of sodium formate on the acetyl chloride) were added thereto. Next, the mixture was agitated for 3 hours and 30 minutes. Then, 110 cc. of water were added and the reaction mixture was allowed to stand overnight at room temperature. Thereafter, the reaction mixture was poured into a water-ice mixture. The precipitate was extracted with ether. The ethereal phases were separated and washed with water, then extracted with N/2 sodium hydroxide-ice mixture. The alkaline phases were acidified with hydrochloric acid to a pH of l, and extracted with ether. The ethereal phases were washed with water, dried and distilled to dryness. The residue obtained was purified by dissolution in hot ethanol, which was then allowed to return to room temperature. Next, the mixture was iced for 30 minutes and vacuum filtered. The precipitate was washed first with iced ethanol, then with petroleum ether and finally dried. 14.72 gm. of 10-hydroxymethylene-13flethyl-17fl-benzoyloxy-des-A-A -gonene-5-one were obtained in the form of clear, yellow crystals, soluble in acetone, chloroform and methanol, and insoluble in water. The product had a melting point of 118 C. and a specific rotation [u] -=+58i2 (c.=0.5% in chloroform).

Analysis.-Calculated for C H O (percent): Molecular weight=366.44. C, 75.38; H, 7.15. Found (percent): C, 75.1; H, 6.9.

This compound is not described in the literature.

TE l i r i 1 A room temperature, under agitation and an atmosphere of nitrogen, 14.72 gm. of IO-hydroxymethylene- 13fl-ethy1-17(3-benzoyloxy-des-A-A -gonene 5 one were dissolved in a mixture of 75 cc. of dioxane and 75 cc. of ether. A solution of 10.5 gm. of dicyanodichlorobenzoquinone in 75 cc. of dioxane was added while maintaining the interior temperature between 8 C. and 10 C. Then, the mixture was agitated over a period of 45 minutes at room temperature. Next, the reaction mixture was poured into an iced solution of sodium bicarbonate and sodium bisulfite and extracted with ether. The ethereal phases were washed first with a mixture of 0.1 N sodium hydroxide and ice, then with water and finally distilled to dryness. 7.47 gm. of raw product were thus recovered, which was purified by chromatography through a. column of alumina and elution with methylene chloride. In this manner, after evaporation of the solvent, 5.33 gm. of 10-formyl-13fl-ethyl-17B-benzoyloxy des A A gonadiene-S-one were obtained, which product was used as such in the next step.

This compound is not described in the literature. STEP C-PREPARATION OF 10-HYDROXYMETI-IYL-13fi ETHYL-lFB-BENZOYLOXY DES A AMLGONADIENE- -ONE At room temperature, under agitation and an atmosphere of nitrogen, 5.42 gm. of -formyl-13fl-ethyl-17flbenzoyloxy-des-A-A -gonadiene 5 one were dissolved in 54 cc. of dioxane. The temperature was brought to +5 C., and 180 mg. of sodium borohydride were added to the solution. The reaction mixture was kept under agitation for one hour, then poured into a water-ice mixture. The mixture was then extracted with methylene chloride. Next, the methylene chloride phases were washed with water, dried and distilled to dryness. The resultant residue was subjected to chromatography through alumina and eluted with methylene chloride. After the evaporation of the solvent, 3.15 gm. of 10-hydroxymethyl-13B- ethyl-17fl-benzoyloxy-des-A-A -gonadiene 5 one were obtained. The product was utilized as such for the following step.

For analysis, the product was recrystallized from ether and petroleum ether. This compound occurred in the form of yellowish crystals, soluble in acetone, chloroform and alcohol, and insoluble in water. It had a melting point of 90 C. and a specific rotation [a] =74i2 c.=O.2% in chloroform).

Analysis.--Calcd for C H 0 (percent): Molecular weight- 366.44. C, 75.38; H, 7.15. Found (percent): C, 75.2; H, 7.3.

This compound is not described in the literature.

STEP DPREPARATION 0F 13fl-EI'HYL-17B-BENZOYL- OXY-Z-OXA-A -GONATRIE'NE-3 ONE (1) Preparation of the zinc reactant: Under an atmosphere of nitrogen, 13 gm. of zinc and 25 mg. of mercuric chloride in 50 cc. of methylal were heated to reflux. Then, 11 cc. of ethyl bromoacetate were added and the reflux was maintained for minutes. Thereafter, 50 cc. of methylal were added and the reaction mixture was again refluxed for an additional 15 minutes. Then the excess of zinc was decanted, thus obtaining a clear solution of zinc derivative of ethyl bromoacetate.

(2) Condensation: At room temperature, under agitation and an atmosphere of nitrogen, 940 mg. of 10-hydroxymethyl-13fi-ethyl 17B benzoyloxy des A A gonadiene-S-one were dissolved in cc. of tetrahydrofuran. Next, 20 cc. of the solution of the zinc reactant, obtained as described in the preceding, were added and the mixture was refluxed for 3 hours. Thereafter, the mixture was cooled, poured into ice and brought to a pH of 1 by an addition of 2 N hydrochloric acid. The acidified mixture was extracted with methylene chloride containing 10% of methanol, decanted and distilled to dryness. In this manner, 5;hydroxy-5i-carboethoxymethyllO-hydroxymethyl-13B-ethyl 17 ,8 benzoyloxy des A- A -gonadiene was obtained. The product was utilized as such for the next step.

This compound is not described in the literature.

(3) Cyclization into 13B-ethyl-175-benzoyloxy-2-oxa- A -gonatriene-3-0ne: At room temperature, under agitation and an atmosphere of nitrogen, 5-hydroxy-5- 16 carboethoxymethyl-IO-hydroxymethyl 13p ethyl 17B- benzoyloxy-des-A-A -gonadiene, obtained above, was dissolved in 10 cc. of acetic acid. Next, 1 cc. of 2 N hydrochloric acid was added and the reaction mixture was agitated for 2 hours. Thereafter, the reaction mixture was poured into water and extracted with methylene chloride. The organic phases were washed first with water, then with a solution of sodium bicarbonate and again with water. The organic solution was treated with carbon black, filtered and distilled to dryness. The residue was dissolved in hot ether, cooled, isopropyl ether was added and the mixture was iced. The precipitate was vacuum 1 EXAMPLE VII Preparation of l3,8-ethyl-2-oxa-A -gonatriene-l7/i- 01-3-one 1.74 gm. of 135-ethyl-17p-benzoyloxy-2-oxagonatriene-3-one were suspended in 45 cc. of methanol. 1.2 cc. of N-methanolic potassium hydroxide were added thereto and the mixture was refluxed for 2 hours and 30 minutes. Thereafter, the mixture was cooled, brought to a pH of 7 by an addition of acetic acid, then poured into water and extracted with methylene chloride. The organic phases were washed with water, dried and distilled to dryness. The residue thus obtained was dissolved in cc. of hot ether. The solution was concentrated to about 10 cc. Then 5 cc. of isopropyl ether were added and again concentrated to 10 cc. Next, the mixture was allowed to stand for 30 minutes at room temperature, then vacuum filtered. The precipitate was Washed with isopropyl ether and dried. In this manner, 0.99 gm. of ethy1-2-oxa-A -gonatriene-17B-ol-3-one were obtained in the form of pale yellow crystals, soluble in acetone, chloroform and alcohols, and insoluble in water, with a melting point of 143 C. and a specific rotation [a] =+43- :2 (c.=0.5% in chloroform).

Analysis.-Calculated for C H O (percent): Molecular weight=286.37. C, 75.49; H, 7.74. Found (percent): C, 75; H, 7.8.

This compound is not described in the literature.

EXAMPLE VIII Preparation of 13j3-ethyl-17fi-acetoxy-2-oxa-A gonatriene-3-one At room temperature, under agitation and an atmosphere of nitrogen, 0.99 gm. of 1?,[3-ethyl-2-oxa-A gonatriene-l7 8-ol-3-one was dissolved in 9 cc. of pyridine. 4.5 cc. of acetic acid anhydride were added and the reaction mixture was maintained at 45 C. for 2 hours and 30 minutes. The excess of acetic acid anhydride was destroyed by an addition of water. The reaction mixture was poured over a mixture of ice and 2 N hydrochloric acid and adjusted to a pH of 1 by 2 N hydrochloric acid. The acidified solution was extracted with methylene chloride. The organic phases were Washed with water, dried and distilled to dryness. The resultant residue was dissolved in ether at room temperature. Isopropyl ether was added to the reaction mixture, which was allowed to stand for 15 minutes at room temperature; then it was vacuum filtered. The precipitate was washed with isopropyl ether and dried. Thus, 803 mg. of 13,8-ethyl-17fl-acetoxy 2-0xa-A -gonatriene-3-one were obtained. The product had a melting point of 85 C. (Kofler Block) and a spe- 17 cific rotation [a] =-|-75:3 (c.=0.5% in chloroform).

The product occurs in the form of colorless crystals, soluble in chloroform, acetone, alcohol and ether, and insoluble in water.

Analysis.-Calculated for C H O (percent): Molecular Weight=328.41. C, 73.14; H, 7.37. Found (percent): C, 72.9; H, 7.3.

Ultraviolet spectra:

max. at 229-230 mu, E%" =184 }"3,,, =870 This compound is not described in the literature.

EXAMPLE IX Preparation of 13fi-methyl-17fi-benzyloxy-2-oxa-A gonatriene-3-one 'sTEP A: PREPARATION OF ETHYLENEDIOXY-- (ETHYLENEDIOXY) METHYL 13B METHYL 17,6

BENZ/OYLOXSLDES-A-A -GONADIENE 5 gm. of 10-formyl-135-methyl-17B-benzoyloxy-des-A- A -gonadiene-5-one (as described in US. patent application No. 603,094) and 0.15 gm. of paratoluene sulfonic acid were introduced into 150 cc. of chloroform and 15 cc. of ethylene glycol under an atmosphere of nitrogen. The mixture was heated to reflux under agitation for 30 hours; the distillate was dried over a dehydrating agent before being recycled. Then 0.05 gm. of paratoluene sulfonic acid was added and the mixture was again heated to reflux under the previously described conditions for 15 hours. The reaction mixture was cooled, made alkaline by addition of triethylamine and diluted with water. The aqueous phase was extracted with methylene chloride, and the extracts were combined with the organic phase. The organic solution thus obtained was washed with water, dried, and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with an ethyl acetatebenzene mixture (1-9). 2.4 gm. of raw mono-ketal (M.P. 192 C.) were first eluted, then 1.7 gm. of raw diketal (M.P. 175 C.) was collected.

After recrystallization of the raw diketal from ethanol, 1.27 gm. of pure S-ethylenedioxy-lO-(ethylenedioxy) methyl-13B-methyl 17p benzoyloxy-des-A-A -gonadiene, having a melting point of 176 C., was obtained.

Analysis.-Calculated for C H O (percent): Molecular weight=334.40. C, 68.24; H, 7.84. Found (percent): 71.2; H, 7.2.

Ultraviolet spectrum (in ethanol):

max. at 239-240 mg, e=32,850.

STEP B: PREPARATION *OF 5-ETHYLENEDIOXY 10- (ETHYLENEDIOXY) METHYL DES A Ae -GONA- DIENEitfi-OL A mixture of 4.77 gm. of 5-ethylene dioxy-lO-(ethylenedioxy) methyl-l3/3-methyl-17/3-benzoyloxy-des-A-A gonadiene and 48 cc. of a N potassium hydroxide solution in 95% ethanol was heated to reflux for 30 minutes and then 250 cc. of water were added. The reaction mixture was extracted with methylene chloride. The organic phases were washed with water, dried over sodium sulfate, filtered and evaporated to dryness under vacuum to yield 3.8 gm. of raw 17fl-hydroxy derivative. 200 mg. of raw product were pasted in isopropyl ether at reflux temperature. After cooling, the precipitate was filtered, washed with isopropyl ether and dried, whereby 175 mg. (92% yield) of product were obtained. This product was purified by recrystallization from ethyl acetate, thus affording 105 mg. of S-ethylenedioxy-lO-(ethylenedioxy) methyl 135 methyl-des-A-A -gonadiene-175-o1. The product occurred in the form of colorless crystals, soluble in ethanol and methylene chloride, insoluble in water, and

melting at 183 C.

Analysis.-Calculated for C H O (percent): Molecular weight=334.40. C, 68.24; H, 7.84. Found (percent):

max. at 325 m Ultraviolet spectrum (in ethanol):

max. at 247 my, e=23,200

STEP C: PREPARATION OF 5 ETHYLENEDIOXY-IO- (ETHYLENEDIOXY) METHYL 13 3 METHYL 173- BENZYLOXY-DES-A-ABJJ-GONADIENE 8.5 gm. of S-ethylenedioxy-IO-(ethylenedioxy)methyl- 13B-methyl-17B-hydroxy-des-A-A -gonadiene were dissolved in 180 cc. of terahydrofuran. Then 3.2 gm. of a suspension of 50% sodium hydride in parafiin oil were added to the solution, and the Whole was heated to reflux for 30 minutes. Then 12.5 cc. of benzyl bromide were added, and the heating at reflux was continued for a period of minutes. The reaction mixture was cooled to room temperature and poured into a mixture of water, ice and aqueous sodium hydroxide solution. The aqueous phase was extracted with methylene chloride, the extracts were combined, washed with water, dried and concentrated to dryness. The residue was triturated with petroleum ether (B.P. 65-75 C.) to afford 7.65 gm. of S-ethylenedioxy- IO-(ethylenedioxy) methyl-13fl-methyl 17B benzyloxydes-A-A -gonadiene melting at 160 C.

The analytical sample, M.P. 163 C., was obtained by recrystallization from methanol containing 2 parts per thousand of triethylamine.

Analysis.Calculated for C H O (percent): Molecular weight =424.52. C, 73.57; H, 7.59. Found (percent): C, 73.5; H, 7.8.

Ultraviolet spectrum (in ethanol) max. at 246 m e=23,600

STEP D: PREPARATION OF 10 FORMYL-l'afl-METHYL- FIB-BENZYLOXY-DES -A---GONADIENE-5-ONE Under an atmosphere of nitrogen, 7.98 gm. of S-ethylenedioxy-lO-(ethylenedioxy) methyl 13B methyl-17B- benzyloxy-des-A-A -gonadiene were dissolved in 60 cc. of acetic acid, then 20 cc. of water were added and the mixture was stirred at room temperature for 1 hour. Then a water-ice mixture was added, and the precipitate thus formed was vacuum-filtered, washed with water and dried to yield 6.05 gm. of raw l0-formyl-1318-methyl-l7flbenzyloxy-des-A-A -gonadiene-5-one, having a melting point of 120 C., which product was used as such in the next step.

STEP E: 10-HYDROXYMETHYL-1315-ME'1HYL-17fi-BENZ- YLOXY-DESA-A11LGONADIENE-5-ONE Under an atmosphere of nitrogen, 6.84 gm. of raw 10- formyl-l3,8-methyl-17,3-benzyloxy-des-A-A gonadiene- 5-one were dissolved in 70 cc. of dioxane. The mixture was cooled to +10 C., and a cold solution of 0.200 gm. of sodium borohydride in 7 cc. of water was added dropwise. The reaction mixture was stirred for 20 minutes, and 0.020 gm. of sodium borohydride was then added. After an additional stirring at +10 C. for 10 minutes, the mixture was poured into water. The aqueous layer was extracted with methylene chloride the combined extracts were washed, first with water, then with a N/ 10 sodium hydroxide aqueous solution and finally with water. The extracts were dried and concentrated to dryness. The residue was purified by chromatography through silica gel to afford 4.14 gm. of IO-hydroxymethyl-l3B-methyl-17B- benzyloxy-des-A-A gonadiene 5-one, having a melting point of C., which product was used as such in the next step.

STEP F: PREPARATION OF 13B-METHYIr17l3-BE NZ- YLOXY-2-OXAA -GONATRIENE3-ONE (1) Reformatsky reaction-Preparation of S-carbethoxy-methyl-10 hydroxymethyl-13/3-methyl 17 3 benzyloxy-des-A-A -gonadiene-S-ol: 3.5 gm. of 10-hydroxymethyl-l3fi-methyl-l7fi-benzyloxy des-A-A -gonadiene 5-one were dissolved in 35 cc. of benzene and 36.5 cc. of a 0.86 M solution of zinc derivative of ethyl bromoacetate in dimethoxy-methane were added to the solution thus obtained. The reaction mixture was heated to reflux for 30 minutes, then cooled to room temperature and poured into a Water-ice-hydrochloric acid mixture. The

aqueous layer was extracted with methylene chloride, the combined extracts were washed with water, dried and evaporated to dryness giving substantially the -carbethoxymethyl-l O-hydroxymethyl-13 p-methyl-17 8 benzyloxy-des-A-A -gonadiene-S-ol (5 gm. yield).

(2") Acid treatment( a) Treatment with a methanolhydrochloric acid mixture: 5 gm. of the residue obtained under 1) were introduced, under nitrogen, in 50 cc. of methanol, then 7.5 cc. of water and 5 cc. of 35% hydrochloric acid aqueous solution. The reaction mixture was stirred at room temperature for hours. The precipitate was vacuum-filtered, washed and dried to yield 2.5 gm. of a crystalline product, M.P. 115 C., consisting of 12-methoxy-13fi-methyl-17fi-benZyloxy-2-oxa A -gonadiene-3-one. The mother liquors and wash waters were combined and evaporated to dryness thereby affording another 1.5 gm. of the same material.

(b) Treatment with a methanol-acetic acid-hydrochloric acid mixture: 2.45 gm. of said product were introduced, while agitating, into 17 cc. of acetic acid. Then 25 cc. of methanol and 2.5 cc. of 35% hydrochloric acid aqueous solution were added to the solution thus obtained. The reaction mixture was stirred at room temperature for 1 hour, then an ice-water mixture was added. The precipitate thus formed was vacuum-filtered, washed and dried. There were obtained 2.15 gm. of 13/3-methyl-17B-benzyloxy-2-oxa-A -gonatriene-3-one, having a melting point of 134 C.

A sample of this compound was crystallized from ethyl acetate. It had a melting point of 136 C. and a specific rotation [a] =+32.5 (c.=0.5% in chloroform).

Analysis.Calculated for C H O (percent): Molecular weight=362.45. C, 79.52; H, 7.23. Found (percent): C, 79.3; H, 7.2.

Ultraviolet sepctrum (in ethanol): max. at 229I1'1,u., e=6,500 inflection at about 256 to 257 mu, e=3,l80 max. at 325 mu, e=28,400

EXAMPLE X Preparation of 13,8-methyl-17p-hexahydrobenzyloxy- 2-oxa-A -gonatriene-3-one STEP A: 5-ETHYLENEDIOXY 10 (ETHYLENEDIOXY) METHYL 13B METHYL-1'ZB-HEXAHYDROBENZYL- OXY-DES-A-A -GHONADIE'NE By following the procedure of step C of Example IX, 5-ethylenedioxy-10-(ethylenedioxy) methyl 13,8 methyldes-A-A -gonadiene-175-01 was reacted in a dimethyl sulfoxide-tetrahydrofuran mixture with hexahydrobenzyl bromide to give 5-ethylenedioxy-l0-(ethylenedioxy) methyl-13,8-methyl 17,8 hexahydrobenzyloxy des-A- A -gonadiene, having a melting point of 180 C. and a specific rotation [a] =-122 (c.=0.5% in chloroform).

Ultraviolet spectrum (in ethanol):

max. at 247 m e=23,700

This compound is not described in the literature.

STEP B: 10 FORMYL-l3B-METHYL17B-H EXAHYDRO BENZYLOXY-DESA-A -GONADIENE-fi-ONE Following the procedure of step D of Example IX,

S-ethylenedioxy-lO (ethylenedioxy) methyl-13,8-methyl- 17/3-hexahydrobenzyloxy des A-A -gonadiene was converted by acetic acid hydrolysis, into 10-formyl-13,B- methyl-l7/3-hexahydrobenzyloxy des A-A -gonadiene S-one, having a melting point of 107 C. and a specific rotation [a] =ll5 (c.=0.6% in chloroform). This material was used as such in the next step.

STEP C: 1O HYDROXYMETHYL-13B-METHYL-17fi-HEXA- HYDROBENZYLOXYDES-A-M-GONADIENES-ONE By following the procedure of step E of Example IX,

the material obtained under (b) was converted by treatment with sodium borohydride into raw l0-hydroxymethyl-13g-methyl 17,8 hexahydr b nzyloxy des-A- A -gonadiene-5-one, which was used as such for the next step.

STEP D 2, 13B-METHYL-17B-HEXAHYDROBENZYLOXY- 2-OXA-A -G0NATRIEN E-3-ONE 1) Reformatsky reactionPreparation of 5-carbethoxy-methyl-IO-hydroxymethyl 13B methyl-17fi-hexahydrobenzyloxy-des-A-A -gonadiene-S-ol: 1.07 gm. of the material obtained under (C) was dissolved under nitrogen in 20 cc. of tetrahydrofuran; then 14.7 cc. of a 0.85 M solution of zinc derivative of ethyl bromoacetate in dimethoxymethane were added to the solution. The reaction mixture was stirred at room temperature for 30 minutes and then it was poured into water. Methylene chloride was added thereto, and the mixture was acidified with a dilute hydrochloric acid aqueous solution. The organic layer was separated, washed with water, dried and concentrated to dryness to yield 1.5 gm. of material containing substantially S-carbethoxy-IO-hydroxymethyll3fl-methyl 17/3 hexahydrobenzyloxy-des-A-A -gonadiene-S-ol.

(2) Acid treatment: The raw material obtained under (1 was dissolved in 15 cc. of acetic acid under nitrogen, and 1 cc. of a 2 N hydrochloric acid aqueous solution was added. The reaction mixture was stirred at room temperature for 45 minutes, and then poured into water. The aqueous phase was extracted with methylene chloride and the extracts were washed with water, dried and evaporated to dryness. The residue subjected to chromatography through silica gel and to elution with an ethyl acetatebenzene mixture l-9), gave 0.796 gm. of 13B-methyl-l7/3- hexahydrobenzyloxy-2-oxa-A -gonatriene-3-one having a melting point of 92 C.

A sample of this product was again subjected to chomatography and recrystallized from diethyl ether. It melted at 97 to 98 C. and had a specific rotation [u] +22 (c.=0.3% in chloroform).

Analysis.Calculated for C I-1 0 (percent): Molecular weight=368.50. C, 78.22; H, 8.75. Found (percent): C, 78.1; H, 8.8.

Ultraviolet spectrum (in ethanol):

max. at 229 to 230 mu, e=6,220 max. at 326 m e=28,400

EXAMPLE XI Preparation of 13,8-methyl-l7fi-(2'-methyl)allyloxy-2- oxa-A -gonatriene-3-one STEP A: 5ETHYLENEDIOXY 10 (ETHYLENEDI'OXY) METHYL 1313 METHYL 17,8 BENZOYLOXY-DES-A- AM -GONADIENE This compound was obtained as described in Example IX step A.

STEP B: PREPARATION OF 5 ETHYLENEDIOXY 10- (ETHYLENEDIOXY) METHYL METHYLDES-A- AQ'H-GONADIEN'EJ'YB-OL This compound was obtained as described in Example IX step 'B.

STEP 0: 5-ETHYLENEDIOXY 10 (ETHYLENEDIOXY) METHYL 13B METHYL-17B (2' METHYL) ALLYL- OXY-DElS'-A-A 11-G()NADIENZBI 2.4 gm. of a suspension of 50% sodium hydride in mineral oil and 24 cc. of tetrahydrofuran were stirred at room temperature under nitrogen for a period of 5 minutes. A solution of 4.09 gm. of S-ethylenedioxy-10-(ethylenedioxy) methyl-13,B-methy1-des-A-A -gonadiene-17p- 01 in 50 cc. of tetrahydrofurau was added thereto and the whole was heated to reflux for 30 minutes.

A solution of 9 gm. of B-methylallyl chloride in 36 cc. of tetrahydrofuran was then added and the whole was heated to reflux for 18 hours. After cooling, 300 cc. of water were added, and the reaction mixture was extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate, filtered, and eva orated to dryness under vacuum, thus yielding 5.55 gm. of raw 17fl-methylallyl derivative which was recrystallized from isopropyl ether (yield 2.44 gm.).

Another crystallization from isopropyl ether afforded an analytical sample which occurred in the form of colorless needles, soluble in ethanol and methylene chloride and insoluble in water. It melted at 137 C. and had a specific rotation [a] =160i-4 (c.=0.2% in chloroform).

Analysis.-Calculated for C H O (percent): Molecular weight=388.49. C, 71.10; H, 8.30. Found (percent): C, 71.1; H, 8.3.

Ultraviolet spectrum (in ethanol):

max. at 246 to 247 my, e=23,100

This compound is not described in the literature.

STEP D: PREPARATION OF -FORMYL-13B-METHYL- )7%1( I21 ;-METHYL) ALLYLOXY-DES-A-A' -GONADIENE- A solution of 2.2 gm. of S-ethylenedioxy lO-(ethylenedioxy) methyl-13,8-methyl-17B-(2-methyl) allyloxy-des- A-A -gonadiene in 16.5 cc. of acetic acid and 5.5 cc. of water was stirred under nitrogen for 1 hour at room temperature and then poured into 400 cc. of saturated aqueous solution of sodium bicarbonate. The mixture was extracted with methylene chloride, and the extracts were washed with water until the wash waters were neutral, dried over sodium sulfate, filtered and evaporated to dryness. There was obtained 1.73 gm. of 10- formyl 135 methyl-17 642 methyl) alloxy-des-A -gonadiene-S-one which occurred in the form of yellow prisms, soluble in acetic acid and methylene chloride, insoluble in water. The material melted at about 58 C.

Ultraviolet spectrum (in ethanol): max. at 233 my, E=6,450 max. at 309 my; e=19,500

This compound is not described in the literature.

STEP E: PREPARATION OF IO-HYDROXYMEIHYL-Bfi- METHYL17fi-METHYL- (W-METHYL) ALLYLOXY-DE S A-A -GONADIENE-5-0NE 2.92 gm. of 1O-formyl-13B-methyl-17B (2'-methyl) allyloxy-des-A-A -gonadiene-S-one were introduced into 30 cc. of dioxane and 3 cc. of water. After cooling to +8C., 100 mg. of sodium borohydride were added,

the mixture was stirred at +10 C. for a period of 30 minutes, poured into a saturated aqueous solution of sodium chloride and extracted with methylene chloride.

The organic phases were washed with water, dried over sodium sulfate, filtered and evaporated to dryness, thus yielding 2.8 gm. of raw 10-hydroxymethyl derivative which was purified by chromatography through silica gel followed by elution with an ethyl acetate-benzene mixture (5-5). In this way, 1.28 gm. of 10-hydroxymethyl- 13fi-methyl-17B-(2'-methyl) allyloxy-des-A-A -gonadiene-5-one was obtained in the form of colorless crystals, soluble in methylene chloride, benzene and ethyl acetate, insoluble in water, and melting at 102 C.

Ultraviolet spectrum (in ethanol): max. at 309 mu, e=l9,500

This compound is not described in the literature.

STEP F: PREPARATION OF 13B-METHYL-17fi-(2-\/IETH- YL) ALLYLOXY-2-OXA-A -GONATRIENE3-ONE (1) Reformatsky reaction: Under an atmosphere of nitrogen, 1.25 gm. of 10-hydroxymethyl1318-methyl-17fi- (2'-methyl) allyloxy-des-A A9111 gonadiene-S-one, 1.25 gm. of zinc and 0.02 gm. of iodine were introduced into cc. of benzene. Then 1.5 cc. of a solution obtained by dissolving 1.78 cc. of ethyl bromoacetate in 4.5 cc. of benzene was added, and the whole was heated at 105 C. for a period of 10 minutes. The remainder of the solution of ethyl bromoacetate was then added and the reflux was maintained for 20 minutes. The reaction mixture was then cooled and filtered. The filter was washed with 5 cc. of benzene and the combined filtrates were poured into 70 cc. of an -N hydrochloric acid solution.

22 After decantation and extraction with methylene chloride, the organic phases were combined, washed with water till neutrality, dried over sodium sulfate and evaporated to dryness to afford 1.9 gm. of adduct.

(2) Saponification of the adduct: 1.7 gm. of the material obtained under 1) was dissolved at 20 C. in 17 cc. of methanol. Then 2.5 cc. of 8 N potassium hydroxide solution were added and the mixture was heated to reflux, under nitrogen, for 30 minutes. 3.4 cc. of hydrochloric acid were added after cooling and the reaction mixture was then poured into water. The mixture was extracted with methylene chloride, the organic phases were washed with a saturated aqueous solution of sodium bicarbonate, then with water till neutrality, dried over sodium sulfate and evaporated to dryness. There was obtained 1.33 gm. of saponified product.

(3) Cyclodehydration: The material obtained under (2) was dissolved in 7 cc. of methanol and 0.7 cc. of hydrochloric acid and the solution was stirred for 1 hour. The reaction mixture was then poured into water and extracted with methylene chloride. The extracts were washed with a saturated aqueous solution of sodium bicarbonate, then with water until the wash waters became neutral, and evaporated to dryness. There was obtained 1.22 gm. of 2-oxa triene derivative which was subjected to chromatography through silica gel, eluted with an ethyl acetate-benzene mixture (9-1) and recrystallized from cyclohexane and then from ethyl acetate gonatriene-3-one which melted at 108 C.

Analysis.Calculated for C H O (percent): Molecular weight=326.42. C, 77.27; H, 8.03. Found (percent): C, 76.9; H, 7.9. Ultraviolet spectrum (in ethanol):

maX. at 229 to 230 m Ei" =190 max. at 326 to 327 mu, E}' ,=869 or e=28,350

This compound is not described in the literature.

EXAMPLE XII Preparation of 13p-methyl-17B-(methylthio) methoxy-Z- oxa-A -gonatriene-3-one Under an atmosphere of nitrogen, 1.09 gm. of 135- methyl 2 oxa-A -gonatriene-17fi-ol-3-one was dissolved in a mixture of 12 cc. of dimethyl sulfoxide and 8 cc. of acetic acid anhydride. The solution was stirred at room temperature for 17 hours and then poured into a mixture of 120 cc. of saturated aqueous solution of sodium bicarbonate and 120 cc. of ice-water. The mixture was stirred for 1 hour and extracted with diethyl ether, the extracts were dried over sodium sulfate and evaporated to dryness under vacuum to yield 1.072 gm. of raw material which was chromatographed through silica gel and eluted with an ethyl acetatebenzene mixture (60-40). Thus were obtained 110 mg. of 13,8-methyl-17B-(methylthio) methoxy-2-oxa-A -gonatriene-3-one having a melting point of about C.

Ultraviolet spectrum (in ethanol):

max. at 326 to 327 my, El'fi =783 or e=26,200

A further chromatography through silica gel followed by elution with an ethyl acetate-benzene mixture (2-8), and recrystallization from a methylene chloride-isopropyl ether mixture (1-10) afforded the pure product which had a melting point of 106 C. and a specific rotation [a] =+98.5 (c.=0.5% in chloroform).

This compound is not described in the literature.

23 EXAMPLE XIII Preparation of 13B-methyl-l7/3-(3-methyl-2'-butenyloxy)- 2-oxa-A -gonatriene-B-one STEP A: PREPARATION OF 5-EIHYLE'N'EDIOXY 10- (ETHYLENEDIOXY) METHYL 135 METHYL17B-(3 METHYL-2'-BUTENYLOXY)-DES-A-A4':11 GONADIENE 3.4 g. of raw S-ethylenedioxy-IO-(ethylenedioxy) methyl 13,8 methyl des-A-A -gonadiene-17,8-01 (obtained in step B of Example IX) were introduced into 35 cc. of tetrahydrofuran under an atomsphere of nitrogen and then 1 gm. of a suspension of 50% sodium hydride in parafi'in oil was added. The mixture was heated to reflux for 30 minutes. Then 6 gm. of 1-bromo-3-methyl-2-butene were introduced therein and the heating at reflux was continued for 2 hours. The reaction mixture was then cooled and subjected to hydrolysis by adding an aqueous solution of sodium bicarbonate. The aqueous layer was extracted with methylene chloride. The combined extracts were washed with water, dried and concentrated to dryness. The residue was taken up with diethyl ether containing 0.5% of triethylamine. The precipitate was vacuumfiltered, and dried, thus affording 3.61 gm. of raw material which was recrystallized from methanol containing 1 part per thousand of triethylamine. Thus, 1.33 gm. of 5-ethylenedioxy-IO-(ethylenedioxy) methyl-l3B-methyl 17 3 3-methyl-2'-butenyloxy)-des-A-A -gonadiene was obtained, which had a melting point of 144 C. and a specific rotation [u] =-134 (c.=0.5% in chloroform).

Analysis.-Calculated for C H O (percent): Molecular weight=402.5l. C, 71.61; H, 8.51. Found (percent): C, 71.8; H, 8.5.

Ultraviolet spectrum (in ethanol):

max. at 246 mg, e=23,500

This compound is not described in the literature.

STEP B: PREPARATION OF 10-FoRMYL-135-METHYL 17B-(3'-METHYL 2' BUTENYLOXY) DES A GONADIENE-5-ONE Under an atmosphere of nitrogen, 3.4 gm. of raw 5- ethylenedioxy 10 (ethylenedioxy) methyI-IBfl-methyl- 17B (3' methyl 2'-butenyloxy)-des-A-A -gonadiene were stirred until dissolved, in 26.4 cc. of acetic acid. Next, 8 cc. of water were added and stirring was continued for 1 hour at room temperature. The reaction mixture was poured into 400 cc. of a saturated aqueous solution of sodium bicarbonate, and the aqueous phase was extracted with methylene chloride. The extracts were washed with water, dried and evaporated to dryness, thus yielding 2.9 gm. of l-formyl-13B-methyl-17fl-(3'-methyl- 2'-butenyloxy)-des-A-A -gonadiene--one. This product was used as such for the next step.

Ultraviolet spectrum (in ethanol):

max. at 230 m E}'Z ,=l95 max. at 308 m Ei'if' ,=505 or e=15,860

This compound is not described in the literature.

STEP 0: PREPARATION OF HYDOXYMETHYL-lZ-lfi- METHYL-17B-(3'-METHYL 2' BUTENYLOXY)-DES- A-A GONADIENE-El-ONE Under an atmosphere of nitrogen, 2.71 gm. of 10- formyl 13p methyl 17,3-(3-methyl-2'-butenyloxy)- des-A-A -gonadiene-S-one were introduced into 30 cc.

of tetrahydrofuran; the mixture was cooled to +5 C.

and 2.95 gm. of lithium hydridotri isobutoxoaluminate were added thereto. The whole was stirred for 30 minutes at +5 C., then diluted with water and brought to a pH of 3.5 by addition of acetic acid. The aqueous layer was extracted with diethyl ether. The extracts were first washed with an aqueous solution of sodium chloride, then with an aqueous solution of sodium bicarbonate and again with the solution of sodium chloride. The extracts were then dried and evaporated to dryness. The residue was chromatographed over silica gel to afford 1.35 g. of 10- 2'4 hydroxymethyl 13B methyl 17,8 (3' methyl-2'- butenyloxy)-des-A-A -gonadiene-S-one. Ultraviolet spectrum (in ethanol):

max. at 287 to 288 III/4., e=l9,960

This compound is not described in the literature. STEP D: PREPARATION OF 13fi-METHYL-17B-(3-METH- (1) Reformatsky reaction: Under an atmosphere of nitrogen, 1.33 gm. of IO-hydroxymethyl-13B-methyl-l7fl- (3'-me'thyl 2' -butenyloxy)-des-A-A -gonadiene-S-one was dissolved in 20 cc. of tetrahydrofuran. Then 22 cc. of a 0.75 M solution of zinc derivative of ethyl bromoacetate in dimethoxymethane were added to the solution thus obtained. The reaction mixture was agitated for 45 minutes at room temperature. cc. of ice-water were added, the mixture was acidified with 10 cc. of 2 N hydrochloric acid and extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate and evaporated to dryness, thus yielding 1.8 gm. of material which was used as such for the next step.

(2) Acid treatment: Under an atmosphere of nitrogen, l.8 gm. of the material obtained under (1") was dissolved in 25 cc. of acetone, and 5.6 cc. of 2 N hydrochloric acid were added. The mixture was stirred at room temperature for 2 hours, then diluted with water and extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate, treated with charcoal, evaporated to dryness, and subjected to chromatography through silica gel to yield 0.383 gm. of methyl-17,8-(3-methyl-2'-butenyloxy)-2-oxa-A gonatriene-3-one having a specific rotation [a] =-152 $2.5 (c.=0.5% in chloroform).

Ultraviolet spectrum (in ethanol):

max. at 230 m @=6,360 max. at 326 to 327 mp, e=25,550

This compound is not described in the literature.

EXAMPLE XIV Pharmacological Study Determination of the anabolic and androgenic activity The studies were effected according to the technique used by Hershberger (Proc. Soc. Exp. Biol. Med., 83, [1953]), but with a slight modification. Castrated male rats, 25 days old, received the compound studied at daily administration for 10 days with the exception of the 6th day. The animals were treated starting on the day following the castration, and they were sacrificed on the 11th day, 22 to 26 hours after the last administration. An autopsy was performed on each animal at the time of the sacrifice and the organs of interest were removed and weighed, in particular, the raising muscle of the anus (levator ani) and the kidneys for the study of the anabolic and renotropic actions, and the prostate gland and the seminal vesicles for the study of the androgenic efiect.

135-methyl-l7,B-acetoxy 2 cam-A -gonatriene-3- one was administered by subcutaneous means, in solution in olive oil containing 5% of benzylic alcohol, at total doses of 100 and 1000 The compound was also given orally either in olive oil at a total dose of 10007, or as an aqueous suspension (water containing carboxymethyl cellulose) at a total dose of 50007. (Total doses=the goses divided into 9 administrations over a period of 10 ays.)

The following tables summarized the results obtained. In these tables are given, as comparison, the results obtained under the same experimental conditions, with the l9-nor-testosterone acetate administered subcutaneously, in a solution in olive oil containing 5% of benzylic alcohol at total doses of 200 and 1000'; and with the 17a-methyl-19-nor-testosterone administered orally, as an aqueous suspension (water containing carboxymethyl cellulose) at total doses of 10 and 50 mg.

27 These results demonstrate that 13fl-methyl-17fl-acetoxy- 2-oxa-A -gonatriene-3-one presents anabolic and androgenic activities superior to those of 19-nor-testosterone acetate, when subcutaneously administered, and even more distinctly superior to those of the l7a-methy1-19- nor-testosterone when orally administered.

(B) 13/3-METHYL-17fl-(METHOXY)-METHOXY 2 OXA- A 'GONATRIEN E-ZB-ONE 13fl-methyl-17B- (methoxy) methoxy 2 oxa A gonatriene-3-one, utilized in solution in olive oil, was administered orally at daily doses of 207x and 1007X%)- TAB LE IV Fresh Seminal ievator vesicles, Prostate Lot Daily dose ani, mg. mg. gland, mg.

Controls 20. 9 4. 8. 2

10 X- 42.6 33.0 15. 6 13fi-methyl-17B-ben- 9 zoyloxy-2-oxw 10 loomas. 4 202. 7 14s. 6

10 1 mgx; 53. 3 256. 2 170. 1 Controls 0 19. 3 16. 3 14. 1

13fi-methyl-17B-benl0 zoyloxy-2-oxa- X 44. 4 72. 7 87. 4 gonatriene-done- 9 Controls 100 23.4 7. 6 10. 3 20 X- 35. 7 9. 2 16. 5 l -nor-testosterone 9 acetate 10 TABLE III.ORAL ADMINISTRATION Weight of animals Fresh levator in grams Fresh ani in grams Seminal Proslevator per 1,000 grams vesicles, tate, Lots Daily dose Initial Final ani, mg. of rat mg. mg. Control 0 51 95 20. 7 0. 218 5. 0 8. 0 4 7X10 52 90 26. 5 0. 294 7. 5 12. 2

9 13B-methyl-17B-(meth0xy)- 207X 10 56 89 36. 7 0. 412 9. 9 17. 1

methoxy-2-oxa-A -gonatriene-3-one 9 9 6007 51 77 21. 80 0.283 9. 2 20. 5 17a-methy1-testosterone 3 mg. 49 63 23. 50 0. 373 32. 6 53. 8 15 mg. 46 70 37. 03 0. 529 117. 0 156. 1

(total doses of 100 administrations in the 10 100 and 1 mg. X-

1 mg. and 10 mg, divided into 9 first test) and at the daily dose of (total dose of 200 in the second test. The results were compiled in Table IV, wherein, for the purpose of comparison, the results are given which were obtained with 19-n0r-testosterone acetate administered in daily doses of 10 20 and 100 9 under the same test conditions.

(2) Oral administration: The studied product was administered at daily doses of 1007x 1 mg. and 10 mg.

in the first test.

In a second test it was administered at daily doses of 10 207 X and 2007 X-g- The product was utilized in an oily solution; however, it was not entirely dissolved in the larger doses.

The results obtained were compiled in Table V which, for purposes of comparison, presents those obtained with 17a-methyl-19-nor-testosterone administered in daily doses of and 5 mg.X

under identical test conditions. i y g TABLE V Fresh Seminal levator vesicles, Prostate Lot Daily dose ani, mg. mg. gland, mg.

Controls 10 13. 8 7. 0 9. 0 1007 X- 38. 2 22. 3 37. 6 13fi-methyl-175-benzoy1oxy-2-oxa-A4,9,l1- gonatriene-Ii-one 1 mgxg 51.6 122.5 119.0

10 l0mg.X3- 55. 1 181. 2 140. 8 Controls m 0 19. 3 16. 3 14. 1 13,3-rnethyl-17B-benz- 20v x- 29.6 10. s 15. 0

oyloxy-2-oxa-A4,9,ll- 9 go'notrlene-3-one. 10

200 X; 41. 3 38. 2 47. 7 Controls m 0 12. 8 5.7 10. 3 1mg.X- 32. 7 18. 2 28. 1 17 -methyl-l9-nor- 9 testosterone m fimgxg' 48. 1 36. 8 74. 7

These results demonstrate that 13 B-methyl-17 pbenzoyloxy-2-oxa-A -gonatriene-3one possesses an anabolisant and androgenic activity distinctly superior to that of the comparison products, administered subcutanously as well as orally.

(D) '13B-ETHYL-17B-ACETOXY-2-OXA-A4''1J- GONATRIENE3-ONE 13p-ethyl-17fl-acetoxy-2-oxa-A -gonatriene 3 one utilized as a solution in olive oil :admixed with 5% of benzyl alcohol, was administered subcutaneously at daily doses of 10 10v X- and 100'yX (total doses of 100 and 1 mg. divided into nine administrations over a period of ten days).

The results obtained are compiled in Table VI wherein, for the purpose of comparison, the results obtained with the 19-nor-testosterone acetate, under the same test conditions, administertd at total doses of 2007 and 1007, are presented.

The results demonstrate that l3fl-ethyl-l7fi-acetoxy-2- oxa-A -gonatriene-3-one exhibits at the daily dose of 107, an anabolisant activity far superior to that of l9-nortestosterone acetate at the dose of 207, and that at the dose of 100 the two products show an appreciably uniform activity. Besides, the studied product is considerably more androgenic than the comparison product.

The studied product administered orally under the same test conditions and utilized as a solution in olive oil, proved to be active at the daily dose of As it has been previously mentioned, the compounds of the general Formula I are endowed with interesting pharmacological properties. In particular, they possess an important anabolic action as well as an androgenic action.

They can be utilized for the treatment of disorders of proteinic anabolism, asthenia, underweight, osteoporosis, andropause, senescence, slow consolidation of fractures, metabolic disorders of prolonged corticotherapy, adiposogenital syndrome, functional menometrorrhagia, fibromes, endometriosis, and also as supplemental treatment of breast cancer.

For external application they can be employed as cicatrization agent for wounds or varicose ulcers.

The novel 13,8-R--0X 2 oxa A gonatriene- 3-ones of the general Formula I are used orally, perlingually, parenterally, transcutaneously, rectally or subcutaneously.

They can be prepared in the form of injectable or drinkable solutions or suspensions, put up in ampules, in multiple-dose flacons, in implants, in tablets, in capsules, in coated tablets, in sublingual tablets, in suppositories, in solutions for transcutaneous usage and in creams or pomades.

The useful dosology is controlled between 0.003 mg./ kg. and 0.3 mg./kg. per day in Warm-blooded animals or 0.200 mg. and 20 mg. per day for the adult as a function of the method of administration and of the therapeutic indication.

The preceding specific embodiments are illustrative of the invention. It is to be understood, however, that other expedients known to those skilled in the art may be employed without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. An unsaturated 2-oxa steroid derivative selected from the group consisting of (a) compounds of the formula O CHzX' 3 wherein X is selected from the group consisting of alkoxy having 1 to 4 carbon atoms, cyclohexyl, alkylthio having 1 to 4 carbon atoms, alkenyl having from 2 to 4 carbon atoms and phenyl and (b) compounds of the formula wherein R is alkyl having from 2 to 6 carbon atoms, X is selected from the group consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 3 to 5 carbon atoms, cycloalkyl having from 5 to 7 carbon atoms, phenylalkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 6 to l1 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms.

2. The unsaturated 2-oxa steroid derivative of claim 1, compound (a), werein X is methoxy.

3. The unsaturated 2-oxa steroid derivative of claim 1, compound (a), wherein X is cyclohexyl.

4. The unsaturated 2-oxa steroid derivative of claim 1, compound (b), wherein R is ethyl and X is hydrogen.

5. The unsaturated 2-oxa steroid derivative of claim 1, compound (b), wherein R is ethyl and X is acetyl.

6. The unsaturated 2-oxa steroid derivative of claim 1, compound (b), wherein R is ethyl and X is benzoyl.

7. The unsaturated 2-oxa steroid derivative of claim 1, compound (a), wherein X is l-methyl-vinyl.

8. The unsaturated 2-oxa steroid derivative of claim 1, compound (a), wherein X is Z-methyl-l-propenyl.

9. A process for the production of an unsaturated 2-oxa steroid derivative of the formula wherein R is alkyl having from 1 to 6 carbon atoms, X is selected from the group consisting of hydrogen, alkyl having from 1 to carbon atoms, alkenyl having from 3 to 5 carbon atoms, cycloalkyl having from 5 to 7 carbon atoms, phenylalkyl having from 7 to 11 carbon atoms, cycloalkylalkyl having from 6 to 11 carbon atoms, alkylthioalkyl having from 2 to 5 carbon atoms, alkoxyalkyl having from 2 to 5 carbon atoms, and the acyl of an organic carboxylic acid having from 1 to 18 carbon atoms, which comprises the steps of condensing a IO-hydroxymethyl-des-A-A gonadiene-S-one of the formula HO-CHz wherein R and X have the above-assigned meanings, with a lower alkyl haloacetate in the presence of zinc, reacting the resulting condensation products, a mixture (1) a 5 alkoxycarbonylmethyl hydroxymethyl des-A- A -gonadiene of the formula HO-OHz- Alkyl-O oo-on wherein R and X have the above-assigned meanings and alkyl represents a lower alkyl, and (2) a 2 oxa A gonadiene-ol-El-one of the formula wherein R and X have the above-assigned meanings, with a strong acid, and recovering said unsaturated 2-oxa steroid derivative.

10. The process of claim 9 wherein said strong acid is selected from the group consisting of hydrochloric acid, sulfuric acid, perchloric acid, p-toluene sulfonic acid and methane sulfonic acid.

32 11. A process for the production of an unsaturated 2-oxa steriod derivative of the formula wherein R is alkyl having from 1 to 6 carbon atoms, which comprises the steps of (a) condensing a 10 hydroxymethyl des A 13 gonadiene 5-one of the formula U-OAcyl HO-OH2 Alkyl- O O C C H27 OH (2) 5; 17B hydroxy 2-oxa-A -gonadiene-3-one of the formula wherein R has the above stated meaning, to the action of a strong acid dehydrating agent and (c) recovering said 2-oxa 3-oxa 17fi-hydroxy gonatriene of the formula 12. The process of claim 11 wherein said unsaturated 2-oxa steroid derivative is subjected to the action of an esterification derivative of an organic carboxylic acid having from 1 to 18 carbon atoms selected from the group consisting of the acid, the acid anhydride and the acid chloride.

13. The process of claim 11 wherein said unsaturated 2-oxa steroid derivative is subjected to the action of an etherification agent selected from the group consisting of dialkyl sulfoxide having from 2 to 5 carbon atoms in the presence of an organic carboxylic acid anhydride and alkoxyalkyl halide having from 2 to 5 carbon atoms.

14. The process of claim 11 wherein said strong acid is selected from the group consisting of hydrochloric acid, sulfuric acid, perchloric acid, p-toluene sulfonic acid and methane sulfonic acid.

15. The process of claim 11 wherein said saponifying agent is an alkali metal hydroxide in the presence of a lower alkanol.

References Cited UNITED STATES PATENTS 3,405,141 10/1968 Pappo et a1. 260-343.2

JOHN M. FORD, Primary Examiner U.S. Cl. X.R. 

